I. Field of the Invention
The present invention is related generally to transdermal delivery of active anti-migraine compounds by the use of an applied electro motive force (emf), commonly known as iontophoresis. Specifically, this invention relates to an improved device for the delivery of anti-migraine drugs, particularly triptan serotonin agonists including Sumatriptan and Naratriptan. Further, this invention provides a wearable iontophoresis system, which can be used to provide both rapid pain relief and sustained action for the prevention of pain recurrence.
II. Related Art
The process of iontophoresis was described by LeDuc in 1908 and has since found commercial use in the delivery of ionically charged therapeutic agent molecules such as pilocarpine, lidocaine and dexamethasone. In this delivery method, ions bearing a positive charge are driven across the skin at the site of an electrolytic electrical system anode while ions bearing a negative charge are driven across the skin at the site of an electrolytic system cathode.
Earlier, and some present, iontophoretic devices have been typically constructed of two electrodes attached by adhesive materials to a patient, each connected by a wire to a remote power supply, generally a microprocessor-controlled electrical instrument.
More recently, self-contained wearable iontophoretic systems have been developed. These systems are advantageous in that they do hot have external wires and are much smaller in size. Examples of such systems can be found in a variety of U.S. patents, including U.S. Pat. Nos. 4,927,408; 5,358,483; 5,458,569; 5,466,217; 5,533,971; 5,605,536; 5,651,768; 5,685,837; 6,421,561; 6,425,892; 6,653,014; and 6,745,071. These systems are also comprised of two electrodes fixed to patients by means of adhesive materials.
Migraine is a condition that affects approximately 10% of the adult population worldwide, yielding approximately 600 million people with about 28 million in the US alone. (L. Morillo. Migraine headache. Am Fam Physician. 65:1871-1873 (2002); L. E. Morillo. Migraine headache. Clin Evid:1547-1565 (2003); and L. E. Morillo. Migraine headache. Clin Evid:1696-1719 (2004)) Females suffer from migraine headache three fold more frequently than males. (E. Lawrence. Diagnosis and Management of Migraine Headaches. Southern Medical Journal. 97:1069-1077 (2004)) Migraine headache is associated with inflamed and dilated blood vessels leading to severe unilateral pain that worsens with physical activity. (The International Classification of Headache Disorders. Cephalagia. 24, Supplement 1: (2004)) In addition to headache pain, migraine can be associated with a variety of other symptoms, including diarrhea, cold extremities, facial pallor, nausea, vomiting and sensitivity to external stimuli such as light, sounds or odors. Approximately one fifth of migraine patients experience an aura or visual symptoms, such as spots of light, zigzag lines, or a graying out of vision. (Cephalagia (2004) and J. Scholpp, R. Shellenberg, B. Moeckesch, and N. Banik. Early treatment of a migraine attack while pain is still mild increases the efficacy of Sumatriptan. Cephalagia. 24:925-933 (2004))
Migraines: typically last for up to 24 hours, but can range from 4 to 72 hours and patients often experience migraine attacks one to two times per month. Migraines can be triggered by many different factors, including life stressors, certain foods or dietary habits, shifts in circadian rhythms, schedules or sleep patterns and changes in weather such as barometric pressure or altitude as well as cyclic variation in hormonal levels during the menstrual cycle. (Cephalagia (2004) and F. D. Sheftell, R. E. Weeks, A. M. Rapoport, S. Siegel, S. Baskin, and F. Arrowsmith. Subcutaneous Sumatriptan in a clinical setting: the first 100 consecutive patients with acute migraine in a tertiary care center. Headache. 34:67-72 (1994))
Pharmacologic interventions constitute the mainstay of treatment for migraines and are available for both acute treatment (abortive) and prevention (prophylactic). Mild migraine can often be effectively treated with over-the-counter medications including aspirin, acetaminophen, NSAIDs, and combination products that include caffeine.
Triptans are the mainstay of treatment for acute migraine of moderate to severe intensity. (E. Lawrence (2004)) When these agents are used early in the course of an attack, triptans abort more than 80% of migraines within two hours.(J. Scholpp et al. (2004)) However, several different triptan products are available with variation in the efficacy and tolerability of different medications in this class. Triptans are also available in a variety of formulations (oral, dissolvable tablet, nasal spray and injectable). Non-oral formulations are typically used for patients with gastrointestinal symptoms of nausea or vomiting and/or when a more rapid onset of action is desired.
Triptans are thought to work by activating serotonin (5-HT) receptors on trigeminovascular nerve endings, inhibiting the release of neurotransmitters that cause painful cranial vasodilatation. (C. M. Sumatriptan.) Furthermore, triptans produce active vasoconstriction and may relieve symptoms of migraine by stimulating 5-HT receptors on cranial vessels. Sumatriptan is the most widely prescribed triptan, comprising roughly half of all triptan prescriptions between 2002 and 2004.
Currently marketed Sumatriptan formulations each have advantages and disadvantages. The injection and intranasal formulations offer rapid onset of action and may reduce further gastrointestinal discomfort. The injection also provides a good response in most patients, but yields a higher maximum concentration that may contribute to a higher side effect burden. However, many patients do not like the discomfort and inconvenience of the injection and the bitter taste of the intranasal formulation. The oral formulation offers convenience and ease of use but produces unreliable blood levels and inconsistent response. Recurrence (rebound) occurs with all three Sumatriptan formulations. (P. Tfelt-Hansen. Efficacy and adverse events of subcutaneous, oral, and intranasal Sumatriptan used for migraine treatment: a systemic review based on number needed to treat. Cephalagia. 18:532-538 (1998).) This common problem with recurrence is likely due to persistence of the original event with a time course exceeding the duration of action from the currently available formulations. This is particularly so because Sumatriptan has a serum elimination half-life of only 2 hrs and most of the active drug is eliminated within 4-6 hrs. in the majority of patients.
A recent publication has indicated that Sumatriptan can be transdermally transported effectively using iontophoresis (Femenia-font et al, J. Pharm Sci 94, 2183-2186, 2005). In this study, iontophoretic transport of Sumatriptan was found to be at a rate 385 fold higher than passive transport. U.S. Pat. No. 5,807,571 contemplates both iontophoretic and passive transdermal delivery of Sumatriptan and other serotonin agonists.
Another recent study has concluded that iontophoresis can be useful in the delivery of anti-migraine compounds (reference Vyteris press release, Sep. 20, 2005). In this study, a two-component system comprised of an electronic controller connected by wire to a transdermal patch was used to deliver Zolmatriptan. The company presenting the results from this study has concluded that programmable capability of its iontophoresis units may allow rapid initial delivery for fast action, while a sustained, low level maintenance dose can be utilized for a prevention of headache recurrence. A significant limitation of this device lies in the two-component structure of the delivery system; the wire connections between the controller and patches are a nuisance to the wearer. Additionally, programmable controllers can be expensive if utilized on a single use basis, or lost, contaminated, broken, etc. if utilized on a reusable basis.
Others have speculated that two-step delivery profiles can be useful an iontophoretic device with rapid onset and sustained action. For example, U.S. Pat. No. 5,207,752 describes a two-stage iontophoretic delivery process that can be utilized to create a drug delivery profile with a first stage in order to rapidly to reach therapeutic level, and an appropriately timed second stage at a lower delivery rate to maintain the blood levels at the therapeutic level. While theoretically sound, this technique will be difficult to use in practice, because the attainment and maintenance of the therapeutic level will have unique timing requirements for each individual patient. Body sizes, drug metabolism, therapeutic blood level, etc. are critical individual factors which will influence the precise timing necessary to switch from high delivery rates to lower ones.
The '752 patent also describes a means to further enhance the rate of therapeutic response, using a three step process. In this embodiment, a first high level of current is applied so the blood levels will exceed the average required therapeutic blood level, the current is ceased for a time period for the blood levels to reach a minimum necessary blood level, then a low level current is at a third time point in order to maintain a lower therapeutic blood level. While this process can provide an advantage in onset of action, the three-step process will require complex current control mechanisms. Given the low cost requirements for simple, disposable wearable devices, a complex three-step process may render the device cost prohibitive on a practical basis for commercial sale.
Others have disclosed simple, low-cost devices structured for waveform delivery patterns with iontophoresis. U.S. Pat. No. 6,421,561, assigned to the same assignee as the present invention, describes very simple electrical circuits that can be used to create low-cost, disposable patches providing multiple current levels in an automated fashion. That reference describes circuits suitable for use with the present invention.
Thus, given the above, there exists the need for an optimal product that would seek to provide the advantages of rapid, systemic Sumatriptan administration found in an injection without the need for an injection and with a consistent duration of action which exceeds the effective time of an injection course of the patient's migraine.